It is of great advantage to both the patient and the physician that medication be formulated so that it may be administered in a minimum number of daily doses from which the drug is uniformly released over a desired extended period of time. This effect is accomplished using sustained or slow release compositions. Sustained or slow release compositions containing pharmaceutical medicaments or other active ingredients are designed to contain higher concentrations of the medicament and are prepared in such a manner as to effect sustained or slow release into the gastrointestinal digestive tract of humans or animals over an extended period of time.
Well absorbed oral sustained or slow release therapeutic drug dosage forms have inherent advantages over conventional, immediate release dosage forms. The advantages include less frequent dosing of a medicament and resultant patient regime compliance, a more sustained drug blood level response, therapeutic action with less ingested drug and the mitigation of side effects. By providing a slow and steady release of the medicament over time, absorbed drug concentration spikes are mitigated or eliminated by effecting a smoother and more sustained blood level response.
For this purpose, a controlled release formulation has to meet some criteria; namely, it must effect an uniform and constant dissolution of the drugs, and it must be effective for an extended period of time. It is also important that such a formulation be simple to make, that the manufacturing process be reproducible and that the product produced by the manufacturing process be uniform. Moreover, if different drugs are used as the active components in the sustained release formulation, it is important that the manufacturing process be easily adaptable to accommodate these various drugs.
Various hydrophilic and hydrophobic materials, including polymers, have been utilized in preparing sustained release formulations. In addition, they have been prepared by various methods, such as solvent evaporation, heat melting, direct compression and wet granulation. Nevertheless, it is well known that the materials used for effecting the controlled release as well as the method of manufacture have a significant effect on the control release performance of the oral dosage form. For example, ethyl cellulose, which is a hydrophobic polymer has been used to effect controlled release of medicaments. However, the release profile is significantly different when it is used as a coating material than when used as a directly compressible powder. Moreover, when matrix type tablets are made with ethyl cellulose using wet granulation methods, the release profile is significantly different from that exhibited by controlled release oral dosage forms prepared by using ethyl cellulose as a directly compressible powder or by using ethyl cellulose as a coating material. Furthermore, if the hydrophobic material is melted in the process of making a sustained release pharmaceutical composition, its release profile is different from that of a controlled release pharmaceutical composition prepared by a different method. These differences in release profile show that the pharmaceutical compositions prepared by the various methods are not the same, but are different.
These differences in release profile are not unique for ethyl cellulose containing pharmaceutical compositions; the release profile of pharmaceutical composition containing other hydrophobic material such as waxes or higher fatty acids or alcohols, and the like, as the controlled release agent are dependent not only upon the identity of the hydrophobic material as controlled release agent, but also upon the method in which the pharmaceutical composition is prepared.
Hydrophobic materials have been used to control the release of medicaments. For example, waxes and lipids have been used as coating material to retard the release of drugs. For instance, the manufacturer of COMPRITOL® 888 (glyceryl behenate), GATTEFOSSE, investigated the effects of coating granules and spheres containing theophylline with COMPRITOL® 888 as a hot melt coating using fluid bed equipment at different concentrations. The wax coating levels of the spherules were 2%, 6% and 10% by weight, respectively. The release profile in water was determined. At 2% levels (w/w) of the wax, 85% of the theophylline was released within one hour. However, at 6% levels of the wax, 55% of the theophylline was released within the first hour, with 35% thereof released in 5 minutes, and at 10% levels (w/w) of the wax, 38% of the theophylline was released within the first hour, with 28% thereof released in 5 minutes. Considering the number of steps used in preparing formulations of this type, this is not an efficient way to formulate controlled released products, and the present inventor sought to find a more efficient process to prepare a controlled release tablet containing a hydrophobic component as the sustained release agent. Moreover, the present inventor also sought to find a method of controlling the release of the drug without placing the wax in a coating, but by blending the hydrophobic material with the drug.
There has been a great deal of literature regarding the use of waxes in controlled release compositions when mixed with medicaments. The common methods of manufacturing sustained release medicaments in oral dosage forms using waxes as the controlled release material admixed with the medicament are (a) melting the drug and wax together, then cooling and milling the melt, and finally tableting after mixing with excipient; (b) using wet granulation techniques, employing an organic solvent as a granulating medium; (c) mixing the drug and waxes in a high shear mixture and using the heat produced during the processing to achieve a homogenous mixture; and (d) using heat radiation to effect melting of the wax in the presence of the drug. All of these methods are cumbersome and can be hazardous.
Most of these techniques use large amounts of waxes to achieve a reasonable controlled release formulation, and the wax is usually present in high concentrations, e.g., greater than 30% (w/w) of the dosage form and in a weight ratio greater than 1:1 relative to the drug. For example, Abdallah in Alex. J. Pharm. 1992, 6, 243–246, evaluated three chosen lipophilic polymers, Precirol® ATO 5 (glyceryl palmito stearate), Precirol® wL-2155 (glyceryl stearate) and Compritol® 888 (glycerol behenate) for the preparation of ibuprofen prolonged release compositions. The tablets were prepared by melting the drug and other ingredients with the polymers, cooling the melt and compressing the cooled melt. He found that granules having a size of 200–315 microns prepared with either of the three polymers in a concentration of either 10 or 20% by weight did not exhibit a release retarding effect; the granule formulations prepared with the above-identified lipids in these amounts released the drug completely within 30 minutes. At 50% level of COMPRITOL® 888, however, the granules exhibited a somewhat suitable sustained release profile. However, making a tablet with such a large amount of wax necessarily makes the tablet too large and thus more difficult to swallow, especially for elder patients. The present inventor thus searched for a means of preparing sustained release formulation containing considerably less hydrophobic material.
Perez, et al. in PRHSJ. 1993, 12, 263–267 investigated the effect of varying wax levels and methods of matrix formulation on drug release. The amount of drug in the formulation was held at 10% w/w, while the wax level was varied from 10% to 50% w/w. The drug formulations were prepared by two different methods. In one method, designated the physical method, the drug, wax and diluent were blended in a Turbula mixer by geometric dilution for 20 minutes and then the mixture was compressed into a tablet. In the second method, designated the solid dispersion method, the wax was melted and the drug in varying concentrations was incorporated into the melted wax. The molten mixture was allowed to cool until it solidified, and then the solidified mass was granulated through a Stokes oscillating granulator equipped with screen No. 12. Perez, et al. found that tablets prepared by the physical method having the same concentration of wax released the drug at a faster rate than the corresponding drug prepared by the solid dispersion method. Tablets prepared by the physical mixture system containing 30% (w/w) wax released about 79% of drug within about six hours, while in tablets containing 50% (w/w) wax, the drug release was 50% after six hours. On the other hand, tablets prepared by solid dispersion containing 30% (w/w) wax showed a drug release of 72% in six hours, while those tablets prepared by the same method containing 50% (w/w) wax released only 30% of the drug in six hours. Further, they showed that a satisfactory release profile was obtained when the ratio by weight of drug to waxy material was greater than 1:1, e.g., at least 3:1.
Moreover, Perez, et al. showed that at 10% levels of wax (w/w), regardless of which method was used, the release profile was unsatisfactory; the sustained release formulation released about 80% of the drug in about 2 hours when prepared by either method.
The prior art showed that at levels of 30% or higher of the waxy material, acceptable sustained release profiles were obtained, but at lower levels, such as 10%, an unsatisfactory sustained release profile was obtained. Thus, these prior art references teach away from preparing a sustained release formulation containing less than 30% wax.
Reilly, et al. in AAPS 1991 investigated the release profile of acetaminophen at 10% level using glyceryl behenate at various concentrations, 10%, 30% or 50% in spheres and tablets, with the latter being prepared by direct compression or by wet granulation. The reference discloses that simple incorporation of the glyceryl behanate into the spheres did not provide slow release. In the tablets, however, a 10% wax did not provide any sustained release action, but at levels of 30% and 50% by weight (that is, 3:1 or 5:1 weight ratio of glyceryl behanate to drug), the tablets exhibited sustained release action. Moreover, for the tablet formulations, as the amount of wax increased, the amount of sustained release action also increased.
Another investigator Terrier investigated the influence of glycerol palmitostearate on the release of drug. He noted that a tablet containing sodium salicylate as the medicament and glycerol palmitostearate as the excipient in 40% by weight, which was prepared by wet granulation methods, did not exhibit any sustained release. For example, 50% of the drug was released in water after 20 minutes.
The above methods used to prepare the pharmaceutical composition were prepared by methods other than direct compression. However, even if the formulation were prepared by direct compression, the prior art showed that at least 30% of the wax was required in the formulation to effect sustained release. For example, El-Sayed, et al. in S.T.P. Pharma. Sciences, 1996, 6, 398–402 prepared a formulation containing 50% theophylline and 30% glyceryl behenate, HPMC or carbopol, and the remainder excipient. Although the tablet so prepared exhibited sustained release formulation, the present inventor searched for a sustained release formulation containing even less than 30% (w/w) wax and a method for preparing same.
The present inventor has found a way to overcome the shortcomings of the prior art and achieve his objective. More specifically, the present invention provides a means of preparing controlled release dosage forms using a simple manufacturing process such as direct compression which involves compression of the various ingredients after a simple mixing procedure. The present inventor has found that effective sustained release formulations can be prepared in this way which incorporates significantly less hydrophobic material than that used heretofore.